Centre National de la Recherche Scientifique, Institut de Pharmacologie et de Biologie Structurale, Unité Mixte de Recherche 5089, 31077 Toulouse, France.
J Immunol. 2011 Oct 1;187(7):3806-14. doi: 10.4049/jimmunol.1101245. Epub 2011 Aug 31.
Tumor-associated macrophages are known to amplify the malignant potential of tumors by secreting a variety of cytokines and proteases involved in tumor cell invasion and metastasis, but how these macrophages infiltrate tumors and whether the macrophage migration process facilitates tumor cell invasion remain poorly documented. To address these questions, we used cell spheroids of breast carcinoma SUM159PT cells as an in vitro model of solid tumors. We found that macrophages used both the mesenchymal mode requiring matrix metalloproteinases (MMPs) and the amoeboid migration mode to infiltrate tumor cell spheroids. Whereas individual SUM159PT cells invaded Matrigel using an MMP-dependent mesenchymal mode, when they were grown as spheroids, tumor cells were unable to invade the Matrigel surrounding spheroids. When spheroids were infiltrated or in contact with macrophages, tumor cell invasiveness was restored. It was dependent on the capacity of macrophages to remodel the matrix and migrate in an MMP-independent mesenchymal mode. This effect of macrophages was much reduced when spheroids were infiltrated by Matrigel migration-defective Hck(-/-) macrophages. In the presence of macrophages, SUM159PT migrated into Matrigel in the proximity of macrophages and switched from an MMP-dependent mesenchymal migration to an amoeboid mode resistant to protease inhibitors.Thus, in addition to the well-described paracrine loop between macrophages and tumor cells, macrophages can also contribute to the invasiveness of tumor cells by remodeling the extracellular matrix and by opening the way to exit the tumor and colonize the surrounding tissues in an MMP-dispensable manner.
肿瘤相关巨噬细胞通过分泌各种细胞因子和蛋白酶来放大肿瘤的恶性潜能，这些细胞因子和蛋白酶参与肿瘤细胞的浸润和转移，但这些巨噬细胞如何浸润肿瘤，以及巨噬细胞迁移过程是否促进肿瘤细胞浸润，这些问题仍知之甚少。为了解决这些问题，我们使用乳腺癌 SUM159PT 细胞的细胞球体作为实体瘤的体外模型。我们发现巨噬细胞既可以使用需要基质金属蛋白酶（MMPs）的间质模式，也可以使用阿米巴样迁移模式来浸润肿瘤细胞球体。虽然单个 SUM159PT 细胞可以通过 MMP 依赖性间质模式侵袭 Matrigel，但当它们生长为球体时，肿瘤细胞无法侵袭围绕球体的 Matrigel。当球体被巨噬细胞浸润或接触时，肿瘤细胞的侵袭性就会恢复。这依赖于巨噬细胞重塑基质并以 MMP 非依赖性间质模式迁移的能力。当球体被缺乏 MMP 迁移能力的 Hck(-/-)巨噬细胞浸润时，巨噬细胞的这种作用大大减弱。在巨噬细胞存在的情况下，SUM159PT 在巨噬细胞附近迁移到 Matrigel 中，并从 MMP 依赖性间质迁移切换到一种对蛋白酶抑制剂有抗性的阿米巴样模式。因此，除了巨噬细胞和肿瘤细胞之间已被描述的旁分泌环之外，巨噬细胞还可以通过重塑细胞外基质，并以 MMP 非必需的方式为肿瘤细胞离开肿瘤并在周围组织中定植开辟道路，从而促进肿瘤细胞的侵袭性。
